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United States Patent | 5,679,680 |
Wang ,   et al. | October 21, 1997 |
The invention covers a novel series of .alpha.-substituted hydrazides that inhibit both calpain I and calpain II. They are non-peptide irreversible active site inhibitors of calpain. The compounds are useful in the treatment of neurodegenerative disorders including cerebrovascular disorders, brain injury, spinal cord, and peripheral nerve injury, cardiac infarction, cataracts, inflammation, restenosis, muscular dystrophy, and platelet aggregation. Pharmaceutical compositions, methods of using processes for preparing and novel intermediates useful in the processes are also disclosed.
Inventors: | Wang; Kevin Ka-Wang (Ypsilanti, MI); Yuen; Po-Wai (Ann Arbor, MI) |
Assignee: | Warner-Lambert Company (Morris Plains, NJ) |
Appl. No.: | 389525 |
Filed: | February 16, 1995 |
Current U.S. Class: | 514/249; 544/354; 564/434 |
Intern'l Class: | A61K 031/495; C07D 241/54 |
Field of Search: | 544/354 514/249 |
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TABLE I ______________________________________ Inhibitory Activity of .alpha.-Substituted Hydrazides Against Human Calpain I and II IC.sub.50 (.mu.M) IC.sub.50 (.mu.M) Ki/›I! (M.sub.-1 s.sub.-1) Example Calpain I Calpain II Calpain I ______________________________________ 5 0.364 0.590 109 4 0.697 0.574 ND 9 0.486 0.158 63.7 14 8.28 10.84 ND ______________________________________ ND = Not determined.
TABLE II ______________________________________ Inhibitory Activity of .alpha.-Substituted Hydrazide Example 5 Against Various Proteases Protease IC.sub.50 (.mu.M) ______________________________________ Calpain I 0.364 Calpain II 0.590 Cathepsin B >200 Papain 5.6 Trypsin >200 Thermolysin >500 Calmodulin-calcineurin >500 ______________________________________
TABLE III ______________________________________ Inhibitory Activity of .alpha.-Substituted Hydrazides on Spectrin Breakdown in Human Leukemic Molt-4 cells Treated With Calcium Ionophore A23187 Example IC.sub.50 (.mu.M) ______________________________________ 5 25 4 25 9 15 ______________________________________
TABLE IV ______________________________________ Effects of the Compound of Example 5 on Oxygen/Glucose Deprivation Induced LDH Release from Fetal Rat Cerebrocortical Cultures LDH release Conditions (Unit/mL) ______________________________________ Normoxia 46.13 .+-. 6.08 (6) Hypoxia/Hypoglycemia 143.81 .+-. 9.72 (6) The compound of Example 5 57.27 .+-. 8.11 (6)** ______________________________________ The data shown are means and SEM. The number of experiment performed was in brackets. **Significantly different from Hypoxia/Hypoglycemia alone (p < 0.001).
TABLE V ______________________________________ Neuroprotective Effects of the Compound of Example 5 Against AMPA Toxicity to Purkinje Cells in Cerebellar Slices Conditions % Live Purkinje Neurons ______________________________________ Control 94.41 .+-. 0.97 (10) AMPA 13.41 .+-. 2.34 (10) AMPA + the Compound of 51.03 .+-. 4.80 (10)** Example 5 ______________________________________ The data shown are means and SEM. The number of experiment performed was in bracket. **Significantly different from AMPA treatment alone (p < 0.005.).